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Inhibition of P53/miR-34a improves diabetic endothelial dysfunction via activation of SIRT1
Jilin Univ, Peoples R China; Harbin Med Univ, Peoples R China.
Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Jilin Univ, Peoples R China.
Jilin Univ, Peoples R China.
Jilin Univ, Peoples R China.
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2019 (English)In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 23, no 5, p. 3538-3548Article in journal (Refereed) Published
Abstract [en]

Endothelial dysfunction contributes to diabetic macrovascular complications, resulting in high mortality. Recent findings demonstrate a pathogenic role of P53 in endothelial dysfunction, encouraging the investigation of the effect of P53 inhibition on diabetic endothelial dysfunction. Thus, high glucose (HG)-treated endothelial cells (ECs) were subjected to pifithrin-alpha (PFT-alpha)-alpha specific inhibitor of P53, or P53-small interfering RNA (siRNA), both of which attenuated the HG-induced endothelial inflammation and oxidative stress. Moreover, inhibition of P53 by PFT-alpha or P53-siRNA prohibited P53 acetylation, decreased microRNA-34a (miR-34a) level, leading to a dramatic increase in sirtuin 1 (SIRT1) protein level. Interestingly, the miR-34a inhibitor (miR-34a-I) and PFT-alpha increased SIRT1 protein level and alleviated the HG-induced endothelial inflammation and oxidative stress to a similar extent; however, these effects of PFT-alpha were completely abrogated by the miR-34a mimic. In addition, SIRT1 inhibition by EX-527 or Sirt1-siRNA completely abolished miR-34a-Is protection against HG-induced endothelial inflammation and oxidative stress. Furthermore, in the aortas of streptozotocin-induced diabetic mice, both PFT-alpha and miR-34a-I rescued the inflammation, oxidative stress and endothelial dysfunction caused by hyperglycaemia. Hence, the present study has uncovered a P53/miR-34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR-34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2019. Vol. 23, no 5, p. 3538-3548
Keywords [en]
aorta; diabetes; endothelial dysfunction; miR-34a; P53
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-157543DOI: 10.1111/jcmm.14253ISI: 000466841100046PubMedID: 30793480Scopus ID: 2-s2.0-85064820839OAI: oai:DiVA.org:liu-157543DiVA, id: diva2:1328671
Note

Funding Agencies|Cheeloo Young Scholar Program of Shandong University; Natural Science Foundation of Jilin Province [2018SCZWSZX-045]; National Natural Science Foundation of China [81600573, 81700393]; Fund of Key Laboratory of Myocardial Ischemia, Ministry of Education [KF201805]

Available from: 2019-06-22 Created: 2019-06-22 Last updated: 2019-06-25Bibliographically approved

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